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For many years, scientists were able to demonstrate that the immune system was active against cancer, but there was a divide they weren’t able to cross. They couldn’t apply that theory to the treatment of cancer until they learned more about how the immune system controls itself.

Now, that door is open, and a host of new therapies are beginning to pass through it.

Because the immune system is very tightly regulated to prevent it from attacking its host, it tends not to react against a lot of the things that can go wrong within our bodies, including cancer. To create effective immunotherapies, we needed to understand this “tolerance” and figure out how to wipe it away.

Recent insights into that dynamic have resulted in a host of new immunotherapies, including the checkpoint inhibitors Opdivo (nivolumab), Keytruda (pembrolizumab) and Yervoy (ipilimumab). By interfering with the so-called “checkpoint” mechanism that keeps the immune system at bay, these medications free up T cells to attack cancer cells. Other immunotherapy types include vaccines, bispecific monoclonal antibodies and laboratory-engineered T cells that are primed to fight cancer.

Due to these recent advances, we now have approved immunotherapies for melanoma, lung cancer and acute lymphoblastic leukemia, and may soon be able to treat other cancer types, including renal and breast, as well as additional hematologic diseases.

Perhaps the greatest appeal of immunotherapy is its lasting effect. Once the immune system has been programmed to fight cancer, it maintains an active surveillance, just as it does against other infections. Theoretically, after immunotherapy treatment has stopped, a patient’s immune system should remain prepared to fight the disease, even if the illness goes away and then recurs. This would represent a major advance in treatment, since cancers often become resistant to other types of medications, including targeted therapies.

The question we will face in the immediate future is whether we can achieve that lasting effect with the strategies currently available. With that in mind, an important job for researchers will be to determine the ideal length of treatment with some of the new immunotherapies, and whether they may need to be combined with other treatments.

The government, too, will play an important role in immunotherapy development. While pharmaceutical and biotechnology companies don’t often fund basic immunology research, the U.S. government does, and that contribution has been crucial. These recent successes highlight the need for the government to remain an active player in the area of immunotherapy, and to make the long-term investments needed to effectively fight cancer.

Articles

Editor's Page

Understanding how the immune system controls itself has led to advances in immunotherapy.

Crossing the Divide

The last five years have seen enormous advances in immunotherapy. Consider that three checkpoint inhibitors and a bispecific monoclonal antibody were approved during that half a decade alone, and you’ll get a sense of the rapid acceleration of progress in this important field.

These drugs can mean everything to some patients, especially those who have been treated with other standard therapies for conditions such as melanoma, lung cancer or acute lymphoblastic leukemia, and experienced disease progression nonetheless. In 

, we give you the stories of some of these patients. Peter Daly, for example, after being diagnosed with metastatic melanoma, helped pioneer the use of the checkpoint inhibitor Yervoy (ipilimumab) in a clinical trial in 2004, and is still thriving. And then there’s Maureen O’Grady, who had run out of approved options for her stage 4 lung cancer by 2008. In a trial of the checkpoint inhibitor Opdivo (nivolumab), which has since been approved for the treatment of lung cancer, she saw her disease recede and stabilize.

We don’t share these stories simply because they’re inspiring, but also to demonstrate the great possibility and hope promised by immunotherapy in the treatment of cancer.

, we will expound on that theme with articles about the approved and/or experimental immunotherapies available for the treatment of melanoma, as well as for renal, lung, breast and prostate cancers. We’ll give you a picture of immunotherapy through time, and perspectives on how immunotherapies will fit into cancer treatment plans, who is eligible for these therapies and how patients can get access to them. We’ll round things out by looking closely at the costs of immunotherapy.

We hope these insights will answer your questions about what immunotherapy is, how it works in the body and how it might be able to help you or a loved one through your experience with cancer.

From the Chairman

Patient success stories illustrate the hope promised by cancer immunotherapy.

Great Possibilities

Immunotherapy agents are being used ever more frequently in oncology.

Among them are Yervoy (ipilimumab), which targets the protein CTLA-4 and is approved for the treatment of metastatic melanoma. Keytruda (pembrolizumab) inhibits the activity of the protein PD-1 and is approved for the treatment of unresectable or metastatic melanoma that has progressed on Yervoy and, if applicable, on a BRAF inhibitor.

Opdivo (nivolumab), which also inhibits the activity of PD-1, is approved to treat metastatic melanoma and non-small cell lung cancer. And drugs that inhibit the protein PD-L1 include the experimental atezolizumab (MPDL3280A), MEDI4736 and BMS-936559, being developed for the treatment of several cancer types.

	Q: What are the most common side effects associated with cancer immunotherapies?

	What are the less commonly observed side effects with these agents?

Due to their growing use in cancer treatment, more patients are living with the side effects of these drugs. CURE asked Michael A. Postow, an assistant attending physician in the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York City, what side effects patients and their doctors should watch out for, and how they can be managed.

 For Yervoy, and for PD-1 inhibitors as well, the most common side effect is dermatologic toxicity. Typically, the rashes that people will have are erythematous, a red rash occurring on the trunk, arms or lower extremities. With Yervoy alone, the dermatologic toxicity onset is typically within the first month, even after the first dose of treatment. Rash or dermatologic toxicity, however, can happen at any time after the first dose, and, at least with Yervoy, I have seen them occur after all four doses have been given, even when the patient has tolerated the initial treatment course well.

For Yervoy in particular, a possible side effect is an enterocolitis/colitis-like event, an inflammation of the colon’s lining that typically manifests with abdominal pain and often watery diarrhea. Occasionally there can be blood in the diarrhea, but this is less common. Although less common than skin rash, this is a more dangerous event. This is more common with the Yervoy-type drugs than with the PD-1 drugs, but it can occur with both. If it occurs, the diarrhea will typically set in after the second or third dose.

	What are the general strategies for managing these events?

Although less frequent than colitis and diarrhea, endocrinopathies (hormonal problems such as an overactive or underactive thyroid or underactive pituitary gland) may also occur, as well as hepatitis or inflammation of the liver. The frequency of these events depends how one defines the endocrinopathies and hepatitis and their severity, but generally these would rank as numbers three and four after dermatologic events and diarrhea. One type of endocrinopathy that can be often hard to diagnose is hypophysitis, which is inflammation of the pituitary gland; this may present as headaches, fatigue and other nonspecific symptoms.

Rash is typically managed first with topical corticosteroids, such as triamcinolone cream, hydrocortisone cream or another low-potency corticosteroid. If that is insufficient, some people require oral steroids for very severe rashes, or rashes that affect so much of the body surface area that the cream cannot be applied successfully. Some patients will just have a lacy, faint, erythematous rash that doesn’t bother them, and some patients will be itchy without a rash, which can also be problematic, since people can be very bothered by itching. The maximal treatment one would ever consider for a rash, if it were terrible — which is, fortunately, very rare &mdash; would involve patients coming into the hospital for fluids, electrolyte management and intravenous steroids. In most cases, though, the rashes can be managed and the drug can be continued.

Diarrhea can happen with or without colitis in about a third of patients, and can be significant in about 10 percent of patients. In terms of treatment, first you would ensure that you have excluded other etiologies, for example, 

 or other infectious types of diarrhea. Typical treatment, when you have substantial diarrhea, is oral corticosteroids — prednisone. The Yervoy package insert has algorithms with number of stools per day and so on to recommend discontinuing treatment, but in the broad context, if patients are on steroids for anything more than a mild situation, they generally don’t resume Yervoy. Imodium, other types of anti-diarrheals and a bland diet can also help if the symptoms are mild.

	Are there any rare and/or serious side effects associated with these therapies for which patients and their doctors should be especially vigilant?

Drawing a thyroid stimulating hormone (TSH) level and a liver function test (LFT) are required before starting each dose of Yervoy, and endocrinopathies or hepatitis can often be detected in this way. Patients with events such as LFT abnormalities will often not be symptomatic, and these can usually be corrected with oral steroids. Endocrinopathies can be more difficult to correct. When an endocrinopathy ensues, it’s typically a permanent problem, which means patients will need to take hormone supplements long-term, usually for life.

Pneumonitis, or lung inflammation, with the anti-PD-1 agents but also with Yervoy, is very important because it can, unfortunately and rarely, result in some treatment- related deaths. Recognizing this when it occurs is particularly important now that anti-PD-1 agents like Opdivo are expanding into indications like lung cancer, since these patients may experience, for example, fever or shortness of breath that can be attributable to many other causes within this disease state. Pneumonitis may be treated with steroid immunosuppression or intravenous steroids as needed, and some patients may require bronchoscopy to exclude infection as part of the differential diagnosis. Other rare neurologic conditions may also occur; we have had patients with aseptic meningitis, sensory and motor neuropathies and even Guillain—Barré syndrome, and I mention these because they can be life-threatening if not recognized and treated appropriately.

	Have any notable differences in side effects emerged with the anti-CTLA-4 versus the anti-PD-1/PD-L1 agents?

	Would you expect a different profile of infusion-related side effects when combining these checkpoint inhibitors with (a) each other or (b) other types of immunotherapies?

In addition, patients who have infusion-related side effects requiring steroids or other immunosuppressive agents like Remicade (infliximab) for diarrhea — or sometimes CellCept (mycophenolate mofetil) for transaminitis (elevated liver enzymes) that is not responsive to steroids &mdash; have, in some anecdotal cases, acquired opportunistic infections as a result of their subsequent immunosuppression. We had, for example, a patient with 

 infection that we recently reported in the literature. I would stress that, so far, these have been only isolated cases, and it’s not clear whether this type of event may become an epiphenomenon with increasing use of these agents, but it’s certainly another possible event to be aware of. In patients who are on prolonged steroid courses to treat immune-mediated adverse events, typically we recommend patients to be on 

pneumonia prophylaxis with a medication such as sulfamethoxazole/trimethoprim. There are no other specific vaccines that are necessary during this treatment, but providers and patients should be mindful of the possibility of infection in patients who are immunosuppressed, so that this side effect can be treated.

In my experience, the anti-PD-1/PD-L1 agents have been less likely to cause significant side effects than anti- CTLA-4 agents like Yervoy. There are a lot of theories as to why that might be the case; some think it may be due to the fact that anti-PD-1/PD-L1 agents are acting at the point where the tumor cells are interacting with the T cells, which keeps some of the activation of the immune system localized in the tumor itself, as opposed to more nonspecifically and systemically throughout the body. Others think that agents like Yervoy work in part by depleting regulatory T cells throughout the body, which may also account for the more systemic immune stimulation with Yervoy versus the anti-PD-1/PD-L1 agents.

When combining Opdivo and Yervoy, there seemed to be the same kind of side effects as with either of the two drugs used alone. So not a lot of new side effects with the combination, but the side effects are more frequent when you combine these drugs than when you give them by themselves. As far as combining checkpoint inhibitors with other immunotherapies, interestingly this has been shown to reduce side effects. One study reported a lower rate of significant toxicity when Yervoy was combined with the immunotherapy Leukine (granulocyte-macrophage colony stimulating factor, or sagromostim), compared to Yervoy alone.

Side Note

Rash is the most common side effect of cancer immunotherapies, but patients should watch for more serious issues.

Seeing Red

When she started treatment for allergies, Maureen O’Grady had no inkling that she was about to become a medical pioneer.

That journey began in 2008, when allergy treatment failed and she continued to battle congestion, cough and, especially, shortness of breath. The situation became more alarming when she coughed up blood. Soon thereafter, radiologic tests detected a large mass in her right lung.

“My first oncologist offered me no hope and told me I had 12 to 18 months to live,” says O’Grady, 62, of Milford, Conn., who was diagnosed with advanced-stage lung cancer at age 56 in January 2009. “I changed doctors. I knew I couldn’t change my diagnosis, but I could change the way I was treated.”

Despite a stage 4 diagnosis — with the metastatic cancer in her adrenal glands, liver and heart &mdash; she refused to give up. When one form of chemotherapy failed, she tried another and yet another, then enrolled in clinical trials. “I knew it was risky, but I was fighting for life,” O’Grady says.

Maureen O'Grady, who responded well to Opdivo after being diagnosed with advanced-stage lung cancer, stands with her husband, Tom O'Grady, and a banner depicting a graffiti-style wall that she and other cancer survivors painted.

Finally, she credits an early-phase immunotherapy study with her long-term survival. The drug Opdivo (nivolumab) — which works by taking the brakes off the immune system, allowing it to fight harder against cancer, and which had previously been approved for the treatment of melanoma &mdash; “has reduced and stabilized all areas of disease, with no new growths,” says O’Grady, who received the treatment from June 2010 through June 2012 at Yale Comprehensive Cancer Center in New Haven, Conn. “Physically, I’m feeling well and remain cautiously optimistic, as there is little, if any, history for this drug for lung cancer. I’m one of its pioneers.”

Based on promising results of a multi-center phase 3 trial known as CheckMate-017, the U.S. Food and Drug Administration in March approved Opdivo injection for the treatment of lung cancer, the first immunotherapy to be given the green light in this disease. Opdivo is indicated when metastatic squamous non-small cell lung cancer (NSCLC) has progressed during or after standard platinum-based chemotherapy.

Results of the trial were presented May 29 during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. As one of the most common forms, NSCLC represents about 85 percent of cases. A subtype of this malignancy — squamous cell NSCLC &mdash; accounts for an estimated 25 percent to 30 percent of all lung cancers. For those with distant tumors caused by lung cancer that has spread to other organs, the five-year survival rate is only 4 percent, according to the National Institutes of Health.

While the earliest stages of lung cancer can often be treated with surgery alone with a reasonable chance of cure, they constitute only 15 percent of cases. In most instances, cancer has spread to the lymph nodes or the chest by the time it is detected. More than half of patients are diagnosed in stage 4, when the cancer has already metastasized to distant sites and surgical excision is no longer possible; these cases are not considered curable, though transient responses can be seen with chemotherapy, or when certain mutations are present in the tumor and biological therapies are given initially.

On a global scale, lung cancer claims more lives than any other type of malignancy, resulting in 1.59 million deaths each year, according to the World Health Organization’s latest statistics, released in February. Tobacco use is the most significant risk factor, causing about 70 percent of lung cancer deaths worldwide.

Hope has been offered via a number of immunotherapies recently approved, or being tested, in patients with the disease.

Like Opdivo, Keytruda (pembrolizumab) targets PD-1, an inhibitory T cell co-receptor, or PD-L1, a ligand expressed on the tumor. Interactions between PD-1 and the ligands PD-L1 or PD-L2 are believed to suppress the antitumor immune response. Immune checkpoint inhibitors are intended to impede those interactions, activating T cells — the white blood cells powerful enough to destroy cancer cells.

Keytruda is being tested in a phase 3 trial of patients with PD-L1-positive NSCLC; already approved for the treatment of melanoma, it’s being considered by the FDA under a breakthrough therapy designation, meaning the agency will expedite its review.

Yervoy (ipilimumab), too, is a checkpoint inhibitor approved for the treatment of melanoma, but it works a bit differently, by quieting the CTLA-4 checkpoint on T cells so that they can better fight cancer. It is being tested in phase 3 trials in both NSCLC and small cell lung cancer. Another CTLA-4 antibody, tremelimumab, is in phase 2 testing in patients with mesothelioma.

Immunotherapeutic vaccines include GV1001, which targets telomerase and is being tested in a phase 3 trial in patients with stage 3 NSCLC that can’t be removed surgically. Finally, adoptive T cell transfer is being considered in phase 2 lung cancer trials; this involves removing T cells from a patient, engineering them in a lab to be more active in the fight against cancer, and re-infusing them.

“Immunotherapy is a game-changer, a breakthrough that oncology desperately needs,” says Guneet Walia, director of research and medical affairs at the Bonnie J. Addario Lung Cancer Foundation in San Carlos, Calif. “For the first time, we can begin to talk about long-lasting effects and start thinking about using the ‘C word’ — for cure.”

A tumor doesn’t necessarily need to shrink for a patient to benefit from immunotherapy. “It’s a very important time for patients,” says Roy S. Herbst, a professor and chief of medical oncology at Yale Comprehensive Cancer Center. “Even if the tumor doesn’t change in size, it often stops progressing. Patients live longer because they have a slower progression of their disease.”

What’s unprecedented is, even after the patient stops the treatment, the immune system continues to police cancer cells and mount rigorous attacks. The discovery of immunotherapy is “a quantum leap forward, a moonshot,” Walia says, “adding to our arsenal of agents that are active against even the most intractable cancers for which patients didn’t have many options, especially after their disease progressed upon treatment with the current standard-of-care therapies.” So far, only 20 to 30 percent of cancer patients seem to respond to immunotherapies, and researchers are working to find out why, and how to make the most of the treatments.

Determining which characteristics may predispose patients to derive the most positive outcomes from immunotherapy “is an area of intense investigation that could enable oncologists to deliver the treatment to more patients who could respond successfully and potentially live longer,” says Stephen V. Liu, an assistant professor of hematology/ oncology specializing in thoracic oncology at MedStar Georgetown University Hospital in Washington, D.C.

In CheckMate-017, Opdivo demonstrated markedly improved overall survival compared with chemotherapy in previously treated metastatic squamous NSCLC. Due to the promising results, the study was terminated early, with the FDA deciding to approve the drug more than three months ahead of schedule. Among the 272 participants in the randomized trial, the median overall survival (OS) was 9.2 months in the group of 135 receiving Opdivo versus six months in the group of 137 using the chemotherapy drug docetaxel. Another measure, known as the hazard ratio, calculated a 41 percent decrease in the risk of death for those in the Opdivo group.

Based on the results of a separate phase 3 study, Opdivo is also showing promise in patients with non-squamous NSCLC, and is pending FDA approval for the treatment of that disease type.

In the two trials, investigators noticed differences in the groups of patients who benefited from the drug.

In non-squamous patients, stronger OS outcomes were observed in those who were PD-L1—positive, including a 60 percent reduction in the risk of death for those with the highest PD-L1 levels. But in patients with squamous NSCLC, outcomes favored nivolumab regardless of PD-L1 expression.

Also of note in those with squamous NSCLC was that “there is a subset of patients whose benefit lasts far greater than nine months,” says Liu. “We can’t identify those patients at the beginning, and that’s something that we need to be able to do.”

In the future, with a more reliable biomarker, the response rate may reach 80 percent among patients deemed eligible for the drug, “but we’re clearly not there yet,” says Renato G. Martins, medical director of thoracic, head and neck medical oncology at the Seattle Cancer Care Alliance and a professor of oncology at the University of Washington School of Medicine.

Might PD-L1 have played a role in the response of those excellent Opdivo responders in the squamous NSCLC group? Researchers aren’t yet sure.

“PD-L1 is not a perfect biomarker,” Liu says. “There are multiple ways to detect PD-L1 and different ways to do the test. We’re still learning how to use this marker.”

There is more evidence that the marker is a predictor of successful treatment when the investigational immunotherapy atezolizumab (MPDL3280A) is used in NSCLC.

When compared with docetaxel chemotherapy in the phase 2 POPLAR study, atezolizumab doubled the likelihood of survival in people whose immune cells or advanced NSCLC tumor cells expressed the highest levels of PD-L1. People who had lower levels of PD-L1 expression also benefited from atezolizumab with an improvement in survival; those without any PD-L1 expression had a similar survival with either atezolizumab or docetaxel.

In February, atezolizumab received breakthrough therapy designation from the FDA. Approval is being sought for the treatment of those whose NSCLC, either squamous or non-squamous, expresses PD-L1, and who progressed during or after standard treatments, such as platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease.

Robert “Bob” Schoenbauer, for one, has benefited greatly from the drug.

In late 2013, the now 80-year-old from Waldorf, Md. began coughing, then experiencing shortness of breath and feeling fatigued into the following year. Initial tests in Maryland weren’t definitive, and he and his wife of 60 years, Frances, suspected a winter cold as the culprit, yet were concerned that his worsening condition could be more serious. In March 2014, he was diagnosed with stage 3B NSCLC — a very aggressive form affecting the lungs and lymph nodes; long-term survival isn’t normally expected.

Robert Schoenbauer (second from the left) poses with his wife, Frances, and the bride and groom at a grandson’s wedding.

Schoenbauer entered a trial at Georgetown in which he received weekly infusions of atezolizumab in combination with two chemotherapies, carboplatin and nab-paclitaxel. After three months on this regimen, he has been receiving only atezolizumab every three weeks for about a year in the ongoing phase 1b trial. Investigators still don’t know whether his cancer expressed PD-L1, because that information was blinded as part of the trial.

Almost immediately, Schoenbauer began responding to the immunotherapy administered jointly with chemotherapy. Even his doctors couldn’t believe how quickly his tumor shrank, he says. As for side effects, there were hardly any except for hair loss on his head and body. “Once in a blue moon, I’d get a little tired, when I first started doing the chemo,” Schoenbauer recalls. For the time being, there is no evidence of cancer on his radiologic scans. “I feel absolutely great right now,” he says.

Beyond the expression of PD-L1, there are other biomarkers that indicate who might be a good candidate for immunotherapy.

While the treatment strategy works on both smokers and never-smokers with lung cancer, studies have shown that a higher presence of mutations in the genome — which is typically associated with smoking &mdash; correlates with a better response to treatment.

“Smokers’ genomes are typically associated with higher mutational loads due to exposure to carcinogens in cigarette smoke and, therefore, may respond better than nonsmokers — an example being the promising effects of immunotherapies seen in squamous cell lung cancer and small cell lung cancer, both of which disproportionately affect smokers,” Walia says.

Lung cancer isn’t one disease; it’s a constellation of many different diseases. Comprehensive genomic profiling or a specific molecular diagnostic test may pinpoint an underlying biomarker that, even before the evolution of immunotherapy, had meaning in determining how to treat the disease.

In some cases, a mutation means a patient’s lung cancer is likely to respond to a targeted drug, such as Tarceva (erlotinib), which treats NSCLCs with certain EGFR, or epidermal growth factor receptor, mutations. In those situations, it would typically make the most sense to use targeted treatments before considering immunotherapy, oncologists say. Logically, immunotherapy would come into play after resistance to a targeted drug develops — at least, that’s the thinking at the moment.

“For now, we reserve immunotherapy for use after the standard treatment is not working. But introducing immunotherapy earlier and earlier makes sense. We want to use our best drugs first,” says Georgetown’s Liu. “Targeted drugs have changed the landscape of non-small cell lung cancer, but while they’re very effective, they do not work forever. Eventually, these cancers develop resistance, so using these immunotherapy agents before resistance sets in is really appealing and may be able to provide longer periods of control. But the optimal sequencing of how to use these drugs? We simply don’t know yet.”

Immunotherapy doesn’t work for everyone. About 70 percent to 80 percent of cancer patients don’t respond. Others gain only modest benefits, while overall survival and longterm effects are still unknown. “But this must be considered in light of the fact that these patients don’t really have many options, so any positive effect is a good effect,” says Walia.

That’s only one of the concerns about the use of immunotherapy.

The drugs can cause side effects; with Opdivo, for example, they most commonly involve shortness of breath, fatigue, musculoskeletal pain, cough, decreased appetite, constipation and nausea. The most serious side effects are immune-related and affect healthy organs, potentially including the colon, liver, lung, kidneys and hormone-producing glands, according to the FDA.

Combination regimens of more than one immunotherapy are under evaluation. Administered either concurrently or sequentially, they are more likely to cause toxicities, in some cases severe enough to warrant hospitalization. Many patients also drop out of clinical trials due to serious or lifethreatening complications, Walia cautions.

Patients and their caregivers also should be prepared for a phenomenon called “pseudoprogression.” It’s a false alarm that the disease is progressing when it isn’t. This occurs when immune cells infiltrate tumors to mount an attack, inflating the tumor’s volume before causing it to shrink. The good news is, in most instances, patients with greater pseudoprogression tend to respond better to immunotherapy, she says.

Then there are the high costs of immunotherapy, compounded by the fact that it’s not yet clear how long patients should keep taking these drugs.

As combination regimens of immunotherapy and other standard-of-care regimens continue undergoing investigation, scientific data will increase, Walia says, helping to answer the question: “Are we delivering enough value for the cost? Do four-, five- or 10-month additions in progressionfree and overall survival justify six-figure costs?”

Despite those concerns, oncologists express continued optimism about immunotherapy’s untapped potential. “We do have patients in whom the disease hasn’t returned after they’ve stopped therapy,” Martins says. “Time will tell what that means, but that is not something we used to see with other treatment.”

Herbst, of Yale Cancer Center, adds: “For lung cancer, immunotherapy is really a new paradigm. Actually, for all tumors, immunotherapy is truly revolutionizing the way we care for cancer — using the body’s own immune system to target a tumor.”

Features

For some with lung cancer, immunotherapies are sparking long-lasting responses.

Into the Future

When Kevin Day was diagnosed with advanced renal cell carcinoma in the fall of 2011 at the age of 50, he was told he had just two years to live. His left kidney was removed, and he was put on Sutent (sunitinib) — the targeted drug that is a standard of care in stage 4 or recurrent renal cancer &mdash; but the disease had spread to his lungs and bones and there were no other good options to treat him.

Then Day’s doctor told him about a clinical trial of an immune-boosting drug called atezolizumab (MPDL3280A), which was opening up at the Carolina BioOncology Institute near his home in Charlotte, N.C. Day was accepted into the trial, and within two weeks of starting the drug, his tumors began to shrink. After eight weeks, they were half their original size. He was given the drug every three weeks for a year, by which time all of his tumors had disappeared.

In October of 2013, Day’s cancer relapsed in his spine, so he rejoined the study, which was testing atezolizumab as a single agent for various malignancies. Again, his cancer vanished. Day is still taking the drug as part of the ongoing study, and feeling lucky to be alive.

“The way I describe the drug is it boosts my immune system to fight the cancer,” Day says. “As long as it’s still working, I will stay on it. I can’t even put into words what this opportunity has meant to me.”

Atezolizumab is among an emerging class of immunotherapy treatments called PD-L1 inhibitors. PD-L1 is a protein that is expressed on the surface of some cancer cells, enabling tumors to hide from T cells — important immune cells that have a natural ability to eradicate cancer. Inhibiting PD-L1 and a related protein known as PD-1 effectively unveils cancer cells, taking the brakes off the immune system and unleashing the body’s innate ability to fight cancer.

PD-L1 and PD-1 inhibitors, otherwise known as “checkpoint inhibitors,” are being studied in a variety of tumor types and may be particularly promising in fighting two that can be among the most difficult to treat — advanced renal cell carcinoma and breast cancer.

Kevin Day with his doctor, John Powderly II.

Atezolizumab, which inhibits PD-L1, is a good example. In addition to helping some with renal cancer, like Day, the drug has demonstrated activity in metastatic triple-negative breast cancer. Early results from a phase 1 trial showed that the objective response rate among 54 patients was 19 percent, and that 27 percent of the patients remained progression-free at six months. Side effects most commonly included nausea, loss of appetite, fever and fatigue; 11 percent of patients experienced at least one severe side effect, such as neutropenia.

“This early evidence of clinical activity is very exciting,” says Leisha Emens, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center. “What sets drugs like atezolizumab apart from standard chemotherapy is their ability to create clinical responses that can last longer than the responses typically seen with chemotherapy.”

A similar dynamic is at play with two PD-1 inhibitors, Opdivo (nivolumab) and Keytruda (pembrolizumab), which have already been approved by the U.S. Food and Drug Administration (FDA) to treat melanoma — Opdivo for lung cancer, too. Both are being studied in renal cell carcinoma and breast cancer.

In breast cancer, it’s not yet clear what subset of patients will respond best to PD-1 inhibitors, says Rita Nanda, assistant professor of medicine at the University of Chicago and one of the clinical trial investigators, but oncologists are particularly excited about the prospects for the drugs in metastatic triple-negative breast cancer, where chemotherapy alone is often ineffective.

“The rationale is that [immunotherapy] will add to the benefits of chemo,” Nanda says. “Chemo works by just killing cancer cells directly — it’s directly toxic to the cancer cell. Immunotherapy is indirect. It is waking up the immune system, so it’s really attacking the cancer in a very different way than chemotherapy does.” In a phase 1 study released in December, 18.5 percent of patients with triple-negative breast cancer who had been treated with chemotherapy responded to Keytruda.

Common side effects reported by patients taking checkpoint inhibitors include fatigue, musculoskeletal pain and nausea, according to Marianne Davies, an oncology nurse practitioner at the Smilow Cancer Hospital at Yale-New Haven and an assistant professor at the Yale School of Nursing. These are typically mild, but more serious immune-related adverse events such as pneumonitis, a condition caused by lung inflammation — while infrequent &mdash; can occur. In many cases, immune-related side effects are delayed, appearing even 12 weeks after the start of therapy, Davies says.

While checkpoint inhibitors are exciting, they are far from the only immunotherapy treatments that may work in these cancers, notes John Powderly, president of the Carolina BioOncology Institute and an adjunct professor of medicine at the University of North Carolina and Duke University.

In renal cell and breast cancers, a variety of immunotherapies ranging from monoclonal antibodies like atezolizumab to vaccines are being tested, and not just as standalone treatments but in combination with other immuneboosting drugs or — as in the cases of Opdivo and Keytruda &mdash; with standard- of-care regimens like chemotherapy. The prevailing view is that, ultimately, immunotherapies will be used in combination with other types of treatments or with each other &mdash; the idea being that attacking tumors from many different angles will be the key to eradicating them.

Early combination results are encouraging: A phase 1 study of previously untreated patients with renal cell carcinoma released last fall, for example, showed that atezolizumab combined with Avastin — an anti-angiogenic drug that cuts off the blood supply to tumors and is already approved for the treatment of kidney cancer &mdash; produced an overall response rate of 40 percent.

Serious drug-related side effects were experienced by 30 percent of those taking the combination, including abdominal pain and pneumonia.

Inhibiting a different mechanism that tumors use to evade immune destruction — a protein called indoleamine 2,3-dioxygenase (IDO) &mdash; is another strategy under investigation for breast cancer patients whose disease is tough to beat. One such approach is indoximod, a drug that’s now in phase 2 testing in women with metastatic breast cancer who don’t test positive for HER2, a protein that’s overexpressed in some tumors and that can be targeted with the treatment Herceptin (trastuzumab). The novel drug is being tested in combination with the chemotherapy docetaxel among participants who may have previously taken hormonal therapy, but have not recently received chemotherapy.

What makes IDO intriguing is that it seems to contribute to drug resistance by governing how the immune system responds to dying cells, explains David Munn, professor of pediatric oncology at the Medical College of Georgia. Munn is one of the scientists who pioneered IDO inhibition and he is a consultant to NewLink Genetics, the company that is developing indoximod. “When you give chemotherapy to patients with cancer, a lot of tumor cells die, but often not enough to make the tumor vanish,” Munn says. “Blocking the IDO pathway may help the immune system recognize when tumor cells die after chemotherapy,” so the immune system can help the chemo work better, he says.

In a phase 1 trial, 41 percent of breast cancer patients had stable disease on combination indoximod and docetaxel. Side effects included fatigue, anemia, hyperglycemia, infection and nausea.

Vaccines are also being developed for both breast and renal cancers — some designed to treat the diseases and others to prevent relapses. And while many past attempts at cancer vaccines failed, the newest generation is showing some early signs of success.

One such vaccine, called GVAX, was developed at the Johns Hopkins University’s Sidney Kimmel Comprehensive Cancer Center, and is now in phase 2 testing for the treatment of metastatic HER2-negative breast cancer, typically treated with hormonal therapies and chemotherapy. GVAX is made from breast cancer cell lines that are specially engineered to secrete a protein called GM-CSF (granulocyte macrophage colony-stimulating factor), which recruits a subset of immune cells known as dendritic cells. Those cells activate T cells in the immune system “to search out and destroy tumor cells,” explains Emens. “It’s like a smart bomb for cancer.”

Also focused around dendritic cells is a more personalized approach that is not a vaccine, but rather a reprogramming and reinfusion of a patient’s immune cells: AGS-003, which is in the final stages of testing for the treatment of metastatic renal cell carcinoma. What makes AGS- 003 unique is that it is formulated for each individual patient from his or her tumor and blood cells. RNA (ribonucleic acid) is isolated from the samples and used to program dendritic cells to target the specific antigens — proteins on the surface of tumor cells &mdash; that are unique to each patient’s disease. The cells are mixed with the patient’s blood and re-injected.

The treatment, which is being tested in combination with Sutent, “sensitizes the dendritic cells to the tumor’s signature,” helping them recognize the difference between normal cells and cancerous ones and mount an immune response, says study investigator Gautam Jha, assistant professor in the division of hematology and oncology at the University of Minnesota. The hope, he adds, is that the personalization will create “an immune response that is robust and sustained.”

Two of four patients that Jha treated in a phase 2 study have had near complete response and continued on trial for five years since their diagnoses, he says. While some patients experienced mild injection-site reactions, most side effects observed in the trial were related to Sutent, not to AGS- 003, the study’s researchers reported.

What if the standard of care works but the risk for recurrence is high? Vaccines may, in fact, help lessen the risk that the disease will return. One vaccine being developed to prevent recurrence is NeuVax (nelipepimut-S), which is now in phase 3 testing in survivors of early-stage, node-positive breast cancer with low to intermediate expression of HER2, previously treated with chemotherapy, radiation and hormone therapy. NeuVax consists of a small piece of the HER2 protein attached to GM-CSF. Like other vaccines, it causes only mild side effects such as pain or itching at the injection site.

The combination that makes up NeuVax “is like a spark plug to get the immune response going,” says investigator Elizabeth Mittendorf, associate professor in the department of surgical oncology at the University of Texas MD Anderson Cancer Center. In earlier trials, only 5.6 percent of patients on NeuVax suffered recurrences, while more than 20 percent of control patients — those who weren’t on the vaccine &mdash; saw their cancers return. “It’s very exciting; the vaccine stimulates an immune response that’s potentially lifelong,” Mittendorf says.

That’s a comforting prospect for Diane Altenburg, a participant in the phase 3 NeuVax study. Altenburg survived cancer in one breast 15 years ago, only to see it recur four years later on the other side; she had lumpectomies on both sides. During the NeuVax trial, she received an injection of the vaccine once a month for six months, followed by booster shots every six months for three years. Today she is cancer-free, off all medications and required only to have mammograms every six months. While it is possible that she could have remained disease-free with only standard therapy, this study will assess enough patients to demonstrate whether or not the vaccine can actually improve the cure rate.

“I’m pretty lucky,” says Altenburg, a 67-year-old mother of five and grandmother of 10 who lives in Northern Virginia. “I felt participating in this trial was a viable way of giving back. The vaccine won’t prevent breast cancer, but if it will prevent patients from getting it again, that’s very positive.”

By empowering the body to fight breast and renal cancers, immunotherapies are poised to improve the treatment landscape.

Setting Off a Smart Bomb

The field of prostate cancer vaccines remains an area of active exploration, with clinical trials into the already approved immunotherapy Provenge (sipuleucel-T) continuing and a phase 3 study into PROSTVAC reaching full enrollment. Research into emerging compounds also is under way, including an early study that pairs a vaccine candidate with the immunotherapy Keytruda (pembrolizumab).

Provenge, an autologous dendritic cell vaccine, remains the only therapeutic prostate cancer vaccine with regulatory approval.

Among vaccines under study in prostate cancer, PROSTVAC is a front-runner in the field. The vaccine has yielded promising trial data and falls into the injectable class, involving an initial shot of recombinant poxvirus and several booster shots of recombinant fowlpox.

Both Provenge and PROSTVAC share a common drawback in that clear biomarkers for which patients would benefit most from the therapies have not yet been validated, although this is an area of active investigation, according to Mark Stein, of Rutgers Cancer Institute of New Jersey. Stein is a medical oncologist at the institute and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School. He was involved in a recently concluded phase 2 PROSTVAC trial.

Stein believes that further research on Provenge bears watching and that it could well develop that combining the drug with other therapies will demonstrate additional value. Ongoing clinical trials include phase 2 studies in combination with Yervoy (ipilimumab) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) and with Xtandi (enzalutamide) in men with mCRPC.

Yervoy is an immunotherapy known as a checkpoint inhibitor because it helps lift away natural checks and balances that keep the immune system from launching a full attack on cancer cells. It has been approved by the U.S. Food and Drug Administration for the treatment of melanoma. Xtandi is a hormonal therapy approved for the treatment of mCRPC.

At the 2015 annual meeting of the American Society of Clinical Oncology (ASCO) held May 29 through June 2 in Chicago, investigators in the phase 2 STRIDE trial reported that using Xtandi either in combination with or after Provenge sparked similar immune responses in patients. All patients who took Xtandi after Provenge, compared with 88 percent of those who took the drugs concurrently, experienced side effects, although the incidence of severe adverse events was similar in both arms. Researchers concluded that “both schedules were safe, and (Xtandi) did not impair (Provenge) production or subsequent immune responses.”

Regarding PROSTVAC, the pending results of a large, multicenter phase 3 trial will shed light on whether the vaccine makes any “definitive” contribution to overall survival (OS) in advanced prostate cancer, Stein says. Nearly 1,300 men have enrolled in the global PROSPECT study, which is designed to investigate whether PROSTVAC alone or in combination with granulocyte-macrophage colony-stimulating factor is effective in prolonging OS in men with few or no symptoms from mCRPC.

In addition, a phase 2 study that would combine PROSTVAC with Yervoy is in the planning stages.

Vaccines based on the Listeria bacterium also hold promise and constitute another prong in this field of advancement. Currently, the phase 1 / 2 KEYNOTE-046 trial is combining the experimental Listeria monocytogenes immunotherapy agent ADXS-PSA, which has been modified to target prostate-specific antigen, with the checkpoint inhibitor Keytruda (pembrolizumab). The trial aims to enroll 51 patients with previously treated mCRPC.

Live attenuated Listeria-based vaccines can generate immune system responses that destroy tumor cells, and they have already been studied in pancreatic cancer and mesothelioma. These drugs can help to stimulate the immune responses necessary to facilitate the use of checkpoint inhibitors.

“Listeria-based vaccines are a compelling platform,” Stein says. “It seems to be very immunogenic, safe, and may overcome some of the mechanism that tumors use to hide from the immune system.”

Pipeline

Clinical development of prostate cancer vaccines is moving forward.

Taking a Shot

In reading about cancer these days, it would be hard to miss the news about advances in immunotherapy treatment for diseases including melanoma and lung cancer. After decades of study by scientists, cancer immunotherapies have changed from a promise to a reality. Immunotherapies have recently provided some patients with long-lasting remissions previously considered impossible in their cancer types.

Truly a “precision medicine,” immunotherapy is intended to work with a patient’s immune system to target and eliminate just the cancer cells. The U.S. Food and Drug Administration has approved about 25 immunotherapies to treat melanoma, lung cancer, breast cancer, stomach cancer, lymphoma, leukemia and other cancers.

Because of the unique properties and potential of cancer immunotherapies, these treatments may offer promising alternatives to other kinds of therapeutic approaches. Cancer immunotherapies may not have the same side effects as conventional chemotherapy, such as hair loss and nausea, although they may cause rash, fever or even severe autoimmune reactions. Immunotherapy can complement or synergize with other types of treatments, potentially increasing the chances of success without increasing the overall side-effect burden. And while immunotherapies can take longer to work than other therapies, they may, over time, offer durable and life-extending benefits.

Much more needs to be learned about what types of cancers can be treated with this approach. As a result, patients interested in exploring this option may find that the FDA has not approved immunotherapies to treat their cancer types. That’s where clinical trials might come in.

Joining a trial may offer patients access to new and promising treatments long before they become available commercially — whether those drugs are immunotherapies or other types of cancer medications that may represent important advances in the field. Participating in a trial also provides patients with extra monitoring and care from the trial team. And while patients will have to live with uncertainty about the risks and benefits they face as part of a trial, they will also know they are contributing to vital scientific knowledge that may lead to new and potentially lifesaving treatments for people with all types of cancer.

Many patients are not aware of opportunities to participate in clinical trials. This isn’t just true in immunotherapy — only 3 to 6 percent of eligible cancer patients participate in any kind of clinical trial. It’s true that clinical trials sometimes come with some challenges &mdash; patients may need to travel farther than the hospitals where they are normally treated in order to participate, for instance. Clinical trials have specific inclusion and exclusion criteria, and patients may find that they don’t qualify for certain studies.

But every trial is different, and has different requirements. If one trial isn’t right, continue the search — there are more than 900 clinical trials throughout the United States investigating various immunotherapies across all cancer types and stages. These drugs fall into a variety of classes: monoclonal antibodies, vaccines, oncolytic viruses, adoptive T cell therapies and immune checkpoint inhibitors.

Having funded research in the field of cancer immunotherapy for the last 60 years, the Cancer Research Institute recognizes the vital role that patients play in advancing medicine. To help match more patients with immunotherapy trials, we offer a free Clinical Trial Finder service. Using our service, patients can connect with trained navigators who will help them sort through the wealth of clinical trials out there to find those that may be right for them. Once patients have a trial (or list of trials) that they’re interested in, we encourage them to bring this to their oncologists for discussion.

To reach a cancer immunotherapy clinical trial navigator, contact 855-216-0127 between 8:30 a.m. and 6 p.m. Eastern Time Monday through Friday, or visit us online at www.cancerresearch.org/clinicaltrial- finder. If you are considering a clinical trial of an immunotherapy for yourself or someone you love, this is a good place to start.

Jill O’Donnell-Tormey, Ph.D., is CEO and director of scientific affairs for the Cancer Research Institute, the only nonprofit organization dedicated exclusively to harnessing the immune system’s power to conquer cancer. CRI supports top researchers worldwide, hosts a “think tank” on immunotherapy development, and educates and informs through its websites: cancerresearch.org and, for patients and caregivers, TheAnswerToCancer.org.

Clinical trials can provide patients with early access to promising cancer immunotherapies.

Going On Trial

Hagop Kantarjian is concerned about the high prices of immunotherapies and other cancer drugs, and he’s being anything but quiet about it.

In May 2013, Kantarjian and 120 other doctors and researchers published a commentary in the journal Blood, calling for lower drug prices. The following year, Kantarjian was lead author on the paper “High Cancer Drug Prices in the United States: Reasons and Proposed Solutions,” published in the Journal of Oncology Practice.

“It is our obligation as cancer doctors to keep patients from harm and injustice,” says Kantarjian, a medical oncologist with the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston. “If high prices make drugs unaffordable and inaccessible, thus causing harm, then we should do something.”

Frustrated with the lack of movement on the prices of cancer drugs thus far, the doctor and some of his colleagues have supported a patient-driven online petition (

) asking Congress to give the government, patients and other stakeholders more power when it comes to negotiating prices for cancer drugs.

Currently, prices are set by the companies that make the medications. While drug makers maintain that their prices reflect the value of their immunotherapies, as well as a continuing investment into research aimed at creating new cancer drugs, they point out that they are making it easier for some to afford the medications via financial assistance programs.

Ultimately, Kantarjian and his colleagues want prices that maintain reasonable profits for drug companies while reflecting a drug’s benefit and, yet, remaining affordable to both patients and the health care system.

But who should decide what constitutes “reasonable” or “affordable,” and how? People in all corners of the oncology world are working to answer those questions. Researchers are conducting cost-benefit analyses, oncology organizations are offering advice and patients are being polled about their ability to keep up with prices.

To succeed, “we have to acknowledge that there must be some upper limit to how much we can, as a society, afford to pay to treat each individual patient with cancer,” says Leonard Saltz, a medical oncologist at Memorial Sloan Kettering Cancer Center who has been very involved in the debate over cancer-drug prices. “All of us need to be willing to discuss what that might be.”

HAGOP KANTARJIAN , shown on the job at MD Anderson Cancer Center, wants patients, physicians and the government to have a role in setting the prices of cancer drugs. 

Since 2000, the average price of new cancer drugs has increased from between $5,000 and $10,000 per year to more than $120,000 per year, while the average household income for a family of four has dropped by 8 percent over the last decade to $52,000, Kantarjian and colleagues say. In fact, of 12 new oncology treatments approved in 2012, 11 were priced above $100,000 for one year of treatment, Kantarjian reported in his commentary in Blood.

“Even patients with insurance have out-of-pocket expenses of 20 to 25 percent,” the petition states. “This could force many families to decide whether to pay $25,000 a year for one cancer drug, about half the household income, or forgo the treatment to save the money for other necessities.”

The prices of immunotherapies are becoming an increasingly important part of the equation, since the U.S. Food and Drug Administration has approved five such drugs — including Opdivo (nivolumab), Yervoy (ipilimumab) and Keytruda (pembrolizumab) — within the past few years, and more are in the pipeline. Eventually, some of these may be used as part of more expensive combination regimens.

Costs and sales of oncology drugs and immunotherapeutics are rising more quickly than other biopharmaceutical sectors, notes Saltz. Envisioning the transformation of some cancers into chronic conditions, Citigroup analyst Andrew Baum expects immunotherapy revenues to reach $35 billion within 10 years.

Although these new treatments could radically change the oncology market, there is still a question about whether they will ultimately decrease or increase the cost of treating cancer.

Opdivo, approved for both melanoma and lung cancer, is priced at $12,500 a month, or about $150,000 for a year of treatment; patients take the drug until disease progression or unacceptable toxicity. Keytruda, approved for the treatment of metastatic melanoma, will cost about the same.

Yervoy, approved in 2011 for patients with either previously treated or newly diagnosed advanced melanoma, costs $130,000 for a 12-week course, and some patients take more than one course.

Provenge (sipuleucel-T), a series of three immunotherapy vaccines approved in 2010 based on its ability in a clinical trial to improve median overall survival of men with advanced prostate cancer by 4.1 months, is priced at $93,000 per patient.

The establishment of these prices is likely to support the setting of similar prices for such drugs approved in the future, according to Daniel M. Geynisman, of the Department of Medical Oncology at Fox Chase Cancer Center in Philadelphia, and colleagues in a 2014 review of studies on the cost-effectiveness of cancer immunotherapies.

“A common tactic of pharmaceutical companies is to benchmark prices of new oncologics against existing products and to set the price at a level that is at least as high as the highest priced competing product,” they wrote.

Merck and Dendreon, at least in part, relied on that strategy.

“In pricing Keytruda, we thoroughly considered the unique clinical value of this innovative therapy in advanced melanoma, possible future uses in other cancers and our commitment to access,” says Frank Clyburn, president of Merck Oncology. “The cost of Keytruda is also consistent with other innovative oncology medicines, including the standard of care in advanced melanoma.”

Dendreon considered the millions of dollars spent developing Provenge and seeking its FDA approval; the substantial manufacturing cost for the therapy, which cannot be mass-produced because it incorporates the blood cells of each individual patient; and its benefit-to-risk ratio. “The Provenge price, along with the therapy’s efficacy and safety profile, created a cost per QALY (quality adjusted life year) that was in line with most other therapies available and lower than many,” says Dendreon General Manager Jim Caggiano.

Likewise, Bristol-Myers Squibb considered a host of issues when it set prices for Opdivo and Yervoy, “including the value they deliver to patients and society, the scientific innovation they represent, and the investment required to continue to research and develop innovative medicines in our pipeline,” a company spokesperson says. “As a company, we are sensitive to concerns about the rising costs of health care, including pharmaceuticals, and the importance of continued access to medicines, while recognizing there remain significant unmet needs that require continued development of innovative treatment options.”

All three companies offer and/or donate to programs that may assist patients in paying for the medicines or getting them for free.

Recognizing that putting a dollar value on human life is difficult, and that the figures are debatable, some experts quote the price of one year of extended life to be $50,000 to $60,000. For example, if a drug improves life duration by 50 percent to 90 percent over life expectancy or by six to 11 months, it might be priced at $30,000 to $50,000. Many recent cancer therapies that offer such benefits, however, carry higher price tags.

In their recent review, Geynisman and his co-authors found that, while the cost-effectiveness of many immunotherapies has yet to be studied, most that have been analyzed have high incremental cost-effectiveness ratios (ICERs), meaning that their dollar costs are high in relation to the benefits they offer, when compared against the costs and benefits of standard treatments.

 of a new cancer drug is $120,000 per year, and immunotherapies are no exception. These prices can be difficult for patients to bear, since even those with insurance must typically pay 20 to 25 percent of those costs out-of-pocket.

 and oncology organizations are working to allow stakeholders including the government and patients to have more of a say in what cancer immunotherapies cost.

The authors cited a study that found that Yervoy, at a willingness- to-pay of $146,000 per QALY, was cost-effective for 95 percent of eligible patients compared with best supportive care; however, they noted that the drug’s ICER is “higher than commonly accepted cost-effectiveness thresholds.”

The authors also cited a study that found that Provenge plus standard treatment was not cost-effective at an ICER of $289,964 when compared to standard treatment alone.

With plans afoot for combinations of these drugs with others, and for their extended use in multiple cancers, “overall expenditures on these inhibitors threaten to be unsustainable,” Geynisman and colleagues wrote.

They suggested, however, that prices might drop due to competition among drug makers, clinical trials such as the lung cancer Master Protocol that study a large number of drugs at once, shorter drug-development times due to FDA programs such as the breakthrough designation, the identification of biomarkers that determine which patients will benefit from treatments, and possible reductions in the number or size of doses — for instance, by determining whether or not a tactic like checkpoint inhibition therapy needs to be continued indefinitely.

One thing is certain: As high-cost treatments become standard practice and the proportion of health care resources allocated to these treatments grows, cost-effectiveness of the treatments will need to be transparent to decision-makers. And that includes patients, Geynisman and co-authors assert.

	Oncology Organizations Providing Guidance

“Concerns of financial and emotional distress from the use of costly new cancer drugs that offer marginal benefits, especially among patients with incurable cancers, have prompted the IOM (Institute of Medicine) Committee on the Quality of Cancer Care to recommend providers to communicate information on both total and out-of-pocket costs with patients and to promote early communications of supportive care,” they wrote.

Not all cancer drugs are alike, and those with the most value should command the highest prices and the most comprehensive insurance coverage, some in the health care arena contend. Expert panels organized by the American Society of Clinical Oncology (ASCO) have convened to assess value based on a drug’s comparative effectiveness compared to prevailing therapies, while taking into account toxicity and cost.

Richard Schilsky, ASCO’s chief medical officer, explains that “ASCO is trying to stimulate a conversation about value in cancer care and to provide a framework to guide the discussion between doctors and patients about the value of available treatment options.”

“This is an important initiative being undertaken by ASCO and it is still under development,” Clyburn said. “We look forward to hearing the outcomes and guidance when they become available.”

Memorial Sloan Kettering Cancer Center acted on advice from a committee of its own doctors in 2012 when it decided not to offer a then-new targeted cancer drug — Zaltrap (ziv-aflibercept), for colorectal cancer &mdash; because its price was over $11,000 for a month of treatments and its effectiveness and side effects were similar to those of Avastin (bevacizumab), available at half the price. The drug’s makers, Sanofi and Regeneron, responded by cutting the drug’s price in half.

“If no one else will act, leading cancer centers and other research hospitals should. The future of our health care system, and of cancer care, depends on our using our limited resources wisely,” wrote the doctors, Saltz, Peter B. Bach and Robert E. Wittes, in a New York Times op-ed that year.

Within the oncology community, price tags have sparked debate.

Immunotherapy Special Issue | CURE